In spite of extensive worldwide studies conducted on cancer, it is in practice difficult to cure cancer because of the diversity of cancer itself and the variable pathogenic mechanisms of cancer. There have been incessant attempts made to develop new anti-cancer agents that can overcome the problem with chemoresistance without causing side effects. However, pertinent, efficient drugs still remain in need of development.
The growth of a tumor is incapacitated without the formation of new vessels which supports the growth. As a tumor grows, it rapidly outgrows its blood supply, becoming oxygen insufficient therein. This tumor hypoxia leads to tumor necrosis. In addition, tumor vasculature is destroyed by the pressure of the tumor itself, aggravating the hypoxia. To detour the problem therewith, a tumor expresses proteins necessary for the formation of new vessels to encourage angiogenesis therefore.
So far, much research into the formation of new vessels has resulted in the appearance of various factors involved in angiogenesis or neovascularization, including angiogenic factors, such as VEGF (vascular endothelial growth factor), bFGF (basic fibroblast growth factor), HGF (hepatocyte growth factor), EGF (epithelial growth factor), and angiopoietin, angiogenic factor receptors with tyrosine kinase activity, such as FGFR (fibroblast growth factor receptor), Flk-1/KDR, Flt-1, Flt-3, Tie-1, Tie-2/Tek, and Eph, and endogenous angiogenesis inhibitors, such as angiostatin and endostatin, giving an insight into relationship between angiogenesis or neovascularization and human diseases as well as the mechanism of angiogenesis and neovascularization, and suggesting various methods for regulating angiogenesis. Inter alia, VEGF has aroused a great interest as a target for the selective inhibition of angiogenesis because it is found to have a close correlation with cancer progression and cure rate and its receptor Flk-1/KDR is expressed on endothelial cells with high specificity.
With regard to the relationship between cancer and vessel formation, it was first hypothesized in 1971 by Dr. Folkman that angiogenesis would play an essential role in tumor growth (J. Folkman, Tumor Angiogenesis: Therapeutic Implications. New England Journal of Medicine, 285, 1182-1186, 1971). Since the report on the selective inhibitory effect of fumagillin, a complex biomolecule from a microbial organism, on angiogenesis in 1990, keen attention has been paid to anti-angiogenic agents as therapeutics for cancer (D. Ingber, T. Fujita, et al. Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumor growth. Nature, 348, 555-557, 1990). In addition, endogenous angiogenesis inhibitors, such as angiostatin (M. S. O'Reilly, L. Holmgren, Y. Shing, C. Chen, R. A. Rosenthal, M. Moses, W. S. Lane, Y. Cao, E. H. Sago and J. Forkman., Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis Lung Carcinoma, Cell, 79, 315-328, 1994), and endostatin (M. S. O'Reilly, T. Boehm, C. Chen, et al., Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell, 88, 277-285, 1997) have recently been verified to have potent anticancer activity in animal models, attracting great attention to the use thereof as anticancer agents.
Moreover, angiogenesis inhibitors have advantages as anticancer agents over other anticancer agents in the following aspects: because angiogenesis is essential for the growth and metastasis of cancer, an angiogenesis inhibitor can block cancer growth and metastasis, simultaneously; and an angiogenesis inhibitor targets normal diploid vascular endothelial cells rather than aneuploid, cancer cells, entailing no problems with resistance attributed to the heterogeneity and genetic instability of cancer cells; an angiogenesis inhibitor can exert inhibitory activity against any kind of cancers for the growth of which angiogenesis is indispensible while other anticancer agents show a narrow therapeutic spectrum of specific or several cancers; and since angiogenesis is rare in adults, except for several cases, such as wound healing, menstruation, etc., side effects incurred by other anticancer agents would be greatly reduced upon the use of an angiogenesis inhibitor.
In addition to involvement in the growth and metastasis of cancer, angiogenesis is a direct cause of various angiogenic diseases, including rheumatoid arthritis (Kwon, Ho-Jung, Journal of the Korean Endocrine Society, Vol 16, No. 3, 2001), diabetic retinopathy (Kwoak, No-Hoon, Journal of the Korean Endocrine Society, Vol. 16, No. 3, 2001), ophthalmic diseases such as keratitis, hyperemia, macular degeneration, choroidal neovascularization, and neovascular glaucoma (Y S Kwon, H S Hong, J C Kim, J S Shin, Y S Son. Invest. Ophthalmol. Vis. Sci. February 2005 vol. 46 no. 2 454-460), and corneal neovascularization (Kim, J. H., Lee J. Y., Chung S. K., and Joo C. K. Journal of the Korean Ophthalmological Society, Vol. 40, No. 3, 662-666), psoriasis (D. Creamer, D. Sullivan, R. Bicknell and J. Barker. Angiogenesis Volume 5, Number 4, 231-236), hemangiomas, which may cause the blockage of the airway in lung, threatening life (Birgit M. Kraling et al. American Journal of Pathology, Vol. 148, No. 4, April 1996), and obesity, and thus is expected to be usefully applicable to the prevention and treatment of diseases associated with vascular proliferation as well as cancer.